The intravenous administration of a drug comprised in the form of a solution to treat a site of disease that is distal from the site of injection is common. However, following intravenous administration, the drug spreads throughout the whole body of the subject, and most is excreted, such as through the urine. Thus, a patient may need a relatively large dose of the drug to allow for therapeutic levels at the site of disease. In many cases it may not be possible to administer the required therapeutic dose because an excessively large dose may result in side effects of the drug or uncertainty regarding the safety of a drug. Thus, there is the need for novel methods and materials for delivering therapeutic agents more efficiently to sites of disease with reduction in the risk of side effects.
Colloidal particles (size: 0.02-5 μm as diameter) have been described as drug delivery materials. However, for the most part, they become trapped within the reticuloendothelial system of the liver and spleen when administered to mammals. This has been a major obstacle of efficient drug delivery.
Vesicles have been described as delivery materials which can carry various materials within their inner aqueous phases or bi-layer membranes. However, they are rapidly removed from the blood by becoming trapped within the reticuloendothelial system of the liver and spleen. Accordingly, studies have been performed to extend the residence time of vesicles within blood by adjusting the composition or diameter of the vesicles, or modifying the surface of the vesicles. As a result, it has been reported that the surface modification of vesicles by polyethylene glycol (PEG) chain is effective in reducing the trapping within the reticuloendothelial system of the liver and spleen, and to prolong the residence time of vesicles within blood.
It has been reported that prolonged residency of PEG-vesicles in the blood passively improved the amount of drug delivery to a metabolically active site (for example, tumor), even if it did not use a special accumulation mechanism. This means that the trapping of the intravenously injected vesicles into living tissues is a competitive process. This is known as passive drug delivery, because the uptake into internal organs and tissues of interest is increased by the slower trapping rate of the reticuloendothelial system of the liver and spleen. Passive drug delivery lacks site-directed specificity, and consequently, there is inefficient delivery to specific sites of disease.
Thus, there has been strong interest in the identification of methods to actively direct therapeutic agents to specific sites of disease in a subject. For example, it has been found that cationic vesicles can be utilized to introduce genes into cells. In this regard, various types of cationic vesicles have been proposed, and the possibility of their application in gene therapy is under evaluation. Although the vesicles containing cationic lipids have been demonstrated to accumulate in a targeted site in a simplified model system such as cultured cells, such an effect has not been confirmed in vivo. Although the surface of some active drug delivering materials sometimes shows physiologic activity, the trapping into reticuloendothelial system of the liver and spleen has been an obstacle in vivo.
It has been known that anionic phospholipids (e.g., phosphatidylglycerol, phosphatidylserine and phosphatidylinositol), which have been utilized in anionic vesicles, induce activation of complement or thrombocytopenia (see Reinish et al., Throm. Haemost., 60(3):518-523, 1988; Levine et al., Ann. Intern. Med., 114(8):664-666, 1991). The anionic vesicles sensitized by this immunoreaction are immediately trapped by the phagocytes of the liver or spleen, and can hardly reach bones.
Meanwhile, negatively charged molecules such as phosphoric acid compounds are known to exhibit bone-affinity. This is due to the interaction of these molecules with the positive charge of calcium ions, which exists in the hydroxyapatite of the bone tissues, following intravascular administration. For example, phosphoric acid compounds carrying radioactive labels are utilized in bone scintigraphy. On the other hand, anionic vesicle systems having phosphoric acid residues as charged groups are for the most part removed due to trapping within the reticuloendothelial system of the liver and spleen, and their bone marrow directing property has not been reported. For example, JP-A-2004-203862 discloses vesicles containing phospholipids modified with silyl groups having hydroxyl groups that have affinity to bones. However, no working Examples which demonstrate that the vesicles actually accumulated in bone were set forth.
The bone marrow plays an important role as a hematopoietic organ, and bone diseases such as osteomyelitis and myeloma cause severe morbidity. Since the bone marrow is not an organ to which surgical therapy is an option, the bone marrow diseases are mainly subject to medical treatment, such as by chemotherapy. Further, the bone marrow is highly sensitive to drugs and radiation, and damage to the bone marrow often causes severe side effects. Therefore, there is a great need for drug delivery systems that have the ability to effectively deliver therapeutic agents to the bones or bone marrow. These agents could be bone marrow protecting agents to specifically protect against the toxic effects of chemotherapy or radiotherapy. Bone-targeted agents could also be used as safe and efficient diagnostic agents for the diagnosis of diseases of bone or bone marrow. Presently, there are no effective means for efficiently delivering drugs to the bone marrow. Administration of therapeutic agents to bone marrow using current technology has frequently resulted in unwanted side effects, presenting an obstacle to the therapeutic treatment. Thus, there is the need for more effective methods of targeting therapeutic agents to the bone marrow with minimal side effects.